Dipeptidyl peptidase-IV inhibitory action of Calebin A: An in silico and in vitro analysis

Dipeptidyl peptidase-IV (DPP-IV) inhibitors, the enhancers of incretin are used for the treatment of diabetes. The non-glycaemic actions of these drugs (under developmental stage) also proved that repurposing of these molecules may be advantageous for other few complicated disorders like cardiovascular diseases, Parkinson's disease, Alzheimer's disease, etc. OBJECTIVE: The present study was aimed to investigate the DPP-IV inhibitory potential of Calebin-A, one of the constituents of Curcuma longa.

The phytoconstituent was subjected for various in silico studies (using Schrödinger Suite) like, Docking analysis, molecular mechanics combined with generalized Born model and solvent accessibility method (MMGBSA) and Induced fit docking (IFD) after validating the protein using Ramachandran plot. Further, the protein-ligand complex was subjected to molecular dynamic simulation studies for 50 nanoseconds. And finally, the results were confirmed through enzyme inhibition study.

Insilico results revealed possible inhibitory binding interactions in the catalytic pocket (importantly Glu205, Glu206 and Tyr 662 etc.) and binding affinity in terms of glide g-score and MMGBSA dG bind values were found to be -6.2 kcal/mol and -98.721 kcal/mol. Further, the inhibitory action towards the enzyme was confirmed by an enzyme inhibition assay, in which it showed dose-dependent inhibition, with maximum % inhibition of 55.9 at 26.3 μM. From molecular dynamic studies (50 nanoseconds), it was understood that Calebin A was found to be stable for about 30 nanoseconds in maintaining inhibitory interactions.

From the in silico and in vitro analysis, the current research emphasizes the consideration of Calebin A to be as a promising or lead compound for the treatment of several ailments where DPP-IV action is culprit.